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Molecular Dynamics of Hemoglobin Reveals Structural Alterations and Explains the Interactions Driving Sickle Cell Fibrillation

Maity, D and Pal, D (2021) Molecular Dynamics of Hemoglobin Reveals Structural Alterations and Explains the Interactions Driving Sickle Cell Fibrillation. In: Journal of Physical Chemistry B .

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Official URL: https://doi.org/10.1021/acs.jpcb.1c01684

Abstract

In sickle cell anemia, deoxyhemoglobin deforms RBCs by forming fibrils inside that disintegrate on oxygenation. We studied 100 ns long all-atom molecular dynamics (MD) for sickle and normal hemoglobin fibril models to understand this process, complemented by multiple 1 μs MD for a single tetramer of sickle and normal hemoglobin in deoxy and oxy states. We find that the presence of hydrophobic residues without a bulky side chain at β-6 in hemoglobin is the reason for the stability of the fibrils. Moreover, the free energy landscapes from MD of hemoglobin starting in the tensed (T) state capture the putative transition from T to relaxed (R) state, associated with oxygen binding. The three conformational wells in the landscapes are characterized by the quaternary changes where one αβ dimer rotates with respect to the other. The conformational changes from the oxygenation of sickle hemoglobin hinder the intermolecular contacts necessary for fibril formation. ©

Item Type: Journal Article
Publication: Journal of Physical Chemistry B
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to American Chemical Society
Keywords: Dimers; Free energy; Molecular dynamics; Oxygenation, Conformational change; Deoxyhemoglobin; Fibril formation; Free energy landscape; Hydrophobic residues; Intermolecular contacts; Sickle-cell anemia; Structural alterations, Hemoglobin
Department/Centre: Division of Interdisciplinary Sciences > Computational and Data Sciences
Date Deposited: 03 Dec 2021 07:51
Last Modified: 03 Dec 2021 07:51
URI: http://eprints.iisc.ac.in/id/eprint/70163

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